Nascent Connections: R-Loops and Chromatin Patterning

Abstract

RNA molecules, such as long noncoding RNAs (lncRNAs), have critical roles in regulating gene expression, chromosome architecture, and the modification states of chromatin. Recent developments suggest that RNA also influences gene expression and chromatin patterns through the interaction of nascent transcripts with their DNA template via the formation of co-transcriptional R-loop structures. R-loop formation over specific, conserved, hotspots occurs at thousands of genes in mammalian genomes and represents an important and dynamic feature of mammalian chromatin. Here, focusing primarily on mammalian systems, I describe the accumulating connections and possible mechanisms linking R-loop formation and chromatin patterning. The possible contribution of aberrant R-loops to pathological conditions is also discussed.

Keywords: R-loop; RNA:DNA hybrids; chromatin; gene regulation; genomics; transcription.

Figure 1

(Top) schematic description of co-transcriptional R-loop formation. In most cases, transcription proceeds without R-loop formation (left; thick arrow). In some cases, however, in particular over DNA regions characterized by GC strand asymmetries, the nascent RNA can reanneal and lead to R-loop formation. (Bottom) A brief list of factors know to prevent or facilitate R-loop formation.

Figure 2

Summary of chromatin features associated with R-loop formation at promoter regions. The features were broken down depending on their location. TSS-anchored features typically occur in the immediate surrounding of the promoter region, often at CGI promoters marked by increased CpG density, GC skew and GC content. By contrast, R-loop-anchored features were found to physically coincide with the location of R-loops, typically 1-2 kb downstream of the TSS. Multiple mechanisms are envisioned for coupling R-loop formation to chromatin patterning including the recruitment of chromatin modifying complexes through Rloop binding modules, the prevention of nucleosome re-deposition behind the RNAP machinery, and the co-transcriptional recruitment of chromatin modifying enzymes to transiently stalled RNAP complexes.